Paracetamol (acetaminophen): A familiar drug with an unexplained mechanism of action

Paracetamol (acetaminophen) is undoubtedly one of the most widely used drugs worldwide. As an over-the-counter medication, paracetamol is the standard and first-line treatment for fever and acute pain and is believed to remain so for many years to come. Despite being in clinical use for over a century, the precise mechanism of action of this familiar drug remains a mystery. The oldest and most prevailing theory on the mechanism of analgesic and antipyretic actions of paracetamol relates to the inhibition of CNS cyclooxygenase (COX) enzyme activities, with conflicting views on the COX isoenzyme/variant targeted by paracetamol and on the nature of the molecular interactions with these enzymes. Paracetamol has been proposed to selectively inhibit COX-2 by working as a reducing agent, despite the fact that \u1d62a\u1d62f \u1d637\u1d62a\u1d635\u1d633\u1d630 screens demonstrate low potency on the inhibition of COX-1 and COX-2. \u1d610\u1d62f \u1d637\u1d62a\u1d637\u1d630 data from COX-1 transgenic mice suggest that paracetamol works through inhibition of a COX-1 variant enzyme to mediate its analgesic and particularly thermoregulatory actions (antipyresis and hypothermia). A separate line of research provides evidence on potentiation of the descending inhibitory serotonergic pathway to mediate the analgesic action of paracetamol, but with no evidence of binding to serotonergic molecules. AM404 as a metabolite for paracetamol has been proposed to activate the endocannabinoid and the transient receptor potential vanilloid-1 (TRPV1) systems. The current review gives an update and in some cases challenges the different theories on the pharmacology of paracetamol and raises questions on some of the inadequately explored actions of paracetamol

Loss of hypothermic and anti-pyretic action of paracetamol in cyclooxygenase-1 knockout mice is indicative of inhibition of cyclooxygenase-1 variant enzymes

Paracetamol (acetaminophen), is a centrally-acting antipyretic analgesic drug, which can also lower body temperature. Despite a century of clinical use, its mechanism of pharmacological action has not been completely elucidated. Previously, we demonstrated significant attenuation in the paracetamol induced hypothermia in parallel with its inhibitory action on the synthesis of brain prostaglandin E₂ (PGE₂) in cyclooxygenase-1 (COX-1) knockout mice in comparison to wild-type mice. The above reported pharmacological actions by paracetamol were completely retained in COX-2 knockout mice. We thus concluded that the mechanism of hypothermic action of paracetamol is dependent on inhibition of a COX-1 gene-derived enzyme. In the current investigation, we provide further support for this notion by demonstrating that the paracetamol-induced hypothermia is not mediated through inhibition of COX-1 as neither the COX-1 selective inhibitor, SC560, nor the COX-1/COX-2 dual inhibitor, indomethacin, induced hypothermia at pharmacologically active doses in mice. In addition, using a COX-2-dependent and PGE₂-mediated model of endotoxin-induced fever, paracetamol induced anti-pyretic and hypothermic actions in COX-1 wild-type mice. These effects were fully or partially attenuated in COX-1 knockout mice after prophylactic or therapeutic administration, respectively. Therapeutically-administered paracetamol also reduced hypothalamic PGE₂ biosynthesis in febrile COX-1 wild-type mice, but not in febrile COX-1 knockout mice. In conclusion, we provide further evidence which suggests that the hypothermic and now anti-pyretic actions of paracetamol are mediated through inhibition of a COX-1 variant enzyme

Assessing the outcome of orthognathic surgery by three-dimensional soft tissue analysis

Studies of orthognathic surgery often focus on pre-surgical versus post-surgical changes in facial shape. In contrast, this study provides an innovative comparison between post-surgical and control shape. Forty orthognathic surgery patients were included, who underwent three different types of surgical correction: Le Fort I maxillary advancement, bilateral sagittal split mandibular advancement, and bimaxillary advancement surgery. Control facial images were captured from volunteers from local communities in Glasgow, with patterns of age, sex, and ethnic background that matched those of the surgical patients. Facial models were fitted and Procrustes registration and principal components analysis used to allow quantitative analysis, including the comparison of group mean shape and mean asymmetry. The primary characteristic of the difference in shape was found to be residual mandibular prognathism in the group of female patients who underwent Le Fort I maxillary advancement. Individual cases were assessed against this type of shape difference, using a quantitative scale to aid clinical audit. Analysis of the combined surgical groups provided strong evidence that surgery reduces asymmetry in some parts of the face such as the upper lip region. No evidence was found that mean asymmetry in post-surgical patients is greater than that in controls

Earth-like sand fluxes on Mars

Strong and sustained winds on Mars have been considered rare, on the basis of surface meteorology measurements and global circulation models, raising the question of whether the abundant dunes and evidence for wind erosion seen on the planet are a current process. Recent studies showed sand activity, but could not determine whether entire dunes were moving—implying large sand fluxes—or whether more localized and surficial changes had occurred. Here we present measurements of the migration rate of sand ripples and dune lee fronts at the Nili Patera dune field. We show that the dunes are near steady state, with their entire volumes composed of mobile sand. The dunes have unexpectedly high sand fluxes, similar, for example, to those in Victoria Valley, Antarctica, implying that rates of landscape modification on Mars and Earth are similar

Dipslacement and Mixed Fibre Beam Elements for Modelling of Slender Reinforced Concrete Structures under Cyclic Loads

In this paper, two fibre-based beam elements with enhanced capabilities to consider large displacement s and rotations of slender reinforced concrete members are developed. Fibre beam elements were comprehensively used before to model the behaviour of different structural systems with great accuracy . To upsurge the use of the fibre beam elements in modelling complex reinforced concrete (RC) systems such as slender walls and columns, the elements are improved by including the second order effect. Available research from the literature related to large displacements focused mainly on modelling steel and composite members due to the limitations in their material model behaviour. Conversely, the newly developed elements introduced in this paper can precisely model RC members by accounting for their more complex nonlinear material behaviour under reversed cyclic loads. The first element is formulated using a displacement formulation, while the second element is based on a mixed approach that is computationally more complicated but numerically more efficient . Further, the adopted concrete constitutive law accounts for the effect of compression post-peak softening as well as tension stiffening and degradation under cyclic loads. Several correlation studies are presented to highlight the efficiency of the new elements in modelling slender RC structures

New and novel uses for paracetamol

Paracetamol is used clinically for the treatment of pain and fever. Recent investigations in experimental animals confirmed paracetamol is able to induce potent hypothermia, which is self-reversible and does not lead to any long term toxicities. In this investigation, the authors sought to investigate the mechanism through which paracetamol induces hypothermia in experimental animals. The authors present strong scientific evidence, which demonstrate that the paracetamol-induced hypothermia is mediated through inhibition of the activity of the novel cyclooxygenase (COX) enzyme, COX-3. Further investigations confirm that the paracetamol induced hypothermia is not dependent on interactions with the endocannabinoid or transient receptor potential vanillid-1 (TRPV-1). In addition, co-administration of paracetamol with a cannabinoid agonist resulted in synergistic hypothermia. These data provide a strong rationale for the use of paracetamol along with a cannabinoid agonist for the induction of therapeutic hypothermia in the clinic. Hypothermia is induced for therapeutic purposes in critically ill patients presenting to the clinic with stroke, cardiac arrest or neurotrauma. However, the current approaches used for the induction of therapeutic hypothermia are inefficient, slow and can only be performed in the hospital setting. Most of the neuronal damage takes place during the first hour following the development of critical illness. Having provided evidence on the mechanism of paracetamol-induced hypothermia and the fact that paracetamol and cannabinoid agonists induced synergistic hypothermia, we propose that combination therapy can be translated to the clinic for the induction of therapeutic hypothermia. The advantages that drug-induced therapeutic hypothermia offer over the currently used methods for the induction of therapeutic hypothermia include fact onset of hypothermia; within a few minutes as opposed to 30-60 minutes. This approach offers a cheap and readily available method for the induction of therapeutic hypothermia that has the potential of saving thousands of lives

Current status of hepatocellular carcinoma detection: screening strategies and novel biomarkers.

Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide. Delayed diagnosis is a major factor responsible for the poor prognosis of HCC. Several advances have been made in the field of liver imaging with the use of novel imaging contrasts, improving current imaging techniques with contrast-enhanced computed tomography (CT) and magnetic resonance imaging (MRI), introduction of new technologies such as contrast liver ultrasound, and development of novel biomarkers with the goal of early detection of HCC and improving outcomes of patients with HCC. This review focuses on current surveillance strategies and development of biomarkers with the goal of early detection of HCC

Explicit fiber beam-column elements for impact analysis of structures

The solution of impact problems requires advanced computational techniques to overcome the difficulties associated with large short-duration loads. In this case, the explicit time integration method is typically used, since it provides a stable solution for problems such as the analysis of structures subjected to shock and impact loads. However, most explicit-based finite elements were developed for continuum models such as membrane and solid elements, which renders the problem computationally expensive. On the other hand, the development of fiber-based beam finite elements allows for the simulation of the global structural behavior with very few degrees of freedoms, while accounting for the detailed material nonlinearity along the element length. However, explicit-based fiber beam elements have not been properly formulated, in particular for the case of the emerging force-based beam element. In this paper, two developed fiber plane beam elements that consider an explicit time integration scheme for the solution of the dynamic equation of motion are presented. The first element uses a displacement-based formulation, while the second element uses a force-based formulation. For the latter case, a new algorithm that eliminates the need for iterations at the element level is proposed. The developed elements require the use of a lumped mass matrix and a small time increment to ensure numerical stability. No iterations or convergence checks are required, which renders the problem numerically efficient. The developed explicit fiber beam-column models, particularly the force-based element, represents a simple yet powerful tool for simulating the nonlinear complex effect of impact loads on structures accurately while using very few finite elements. The traditional implicit method of analysis typically fails to provide numerical stable behavior for such short time duration problems. Two correlation studies are presented to highlight the efficiency of the developed elements in modelling impact problems where the strain rate effect is considered in the material models. These examples confirm the accuracy and efficiency of the presented elements

Effects of Women's Schooling on Contraceptive Use and Fertility in Tanzania

This study explores the economic relationships between women's schooling, fertility rates, and contraceptive use in Tanzania where population growth and fertility rates are among the highest in the world and aggravate the already ailing economy. Two models are used: fertility and contraceptive use. This study covers women ages 15 to 49. Drawing on 1996 data from the Demographic and Health Surveys (DHS), the study finds that women's schooling and other socioeconomic variables are important in explaining reproductive behavior. The fertility model indicates that higher education levels are consistently associated with lower fertility rates. Likewise, the contraceptive use model indicates that more education is positively associated with contraceptive use. Both models show that the relations become stronger with higher levels of schooling. The findings indicate that raising women's education levels improves their economic opportunities, increasing the value of their time and, in turn reducing their desire for large families

Inheritance of body weight and breast length at 8 weeks of age in meat type strains of chickens

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